Synthesis and antimalarial activity of new haemanthamine-type derivatives Juan C. Cedrón a,b,c , David Gutiérrez d , Ninoska Flores d , Ángel G. Ravelo a,b,⇑ , Ana Estévez-Braun a,b,⇑ a Instituto Universitario de Bio-Orgánica ‘Antonio González’, Av. Astrofísico Francisco Sánchez 2, 38206, Departamento de Química Orgánica, Universidad de La Laguna, Tenerife, Spain b Instituto Canario de Investigación del Cáncer (ICIC), Spain   c Pontificia Universidad Católica del Perú, Sección Química. Av. Universitaria 1801 San Miguel, Lima 32, Peru d Instituto de Investigaciones Fármaco Bioquímicas, Facultad de Ciencias Farmacéuticas y Bioquímicas, Universidad Mayor de San Andrés, Av. Saavedra 2024, 2° piso, Miraflores, La Paz, Bolivia article info Article history: Received 15 May 2012 Revised 13 July 2012 Accepted 21 July 2012 Available online 31 July 2012 Keywords: Haemanthamine Antiplasmodial activity Amaryllidaceae alkaloids abstract Thirty one derivatives were prepared from the natural alkaloids haemanthamine (1), haemanthidine (2) and 11-hydroxyvittatine (3). They were evaluated for their in vitro antimalarial activity against chloro- quine-sensitive strains of Plasmodium falciparum and some structure–activity relationships were out- lined. For haemanthamine derivatives having a methoxy group at C-3, the presence of a free hydroxyl group at C-11 is important for the activity. The double bond at C-1–C-2 plays also an important role to achieve good inhibitory activity. Compound 35 with two nicotinate groups at C-3 and at C-11 was the most active compound with a IC 50 = 0.8 ± 0.06 lM. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction AIDS, malaria and tuberculosis cause together more than five million deaths per year, especially in developing countries. 1 Although the development of vaccines for these diseases is in pro- gress, treatment for patients depends on the use of specific drugs. Natural products have made and continue to make an immense con- tribution to malaria chemotherapy either directly as antimalarial agents or as important lead compounds for the discovery of more potent antimalarials. 2 Chloroquine, and other quinoline antimalari- als such as primaquine, mepacrine and mefloquine have been main- stays of antimalarial chemotherapy for more than past 40 years. 3 Artemisinin isolated from the Chinese plant Artemesia annua has been used successfully against chloroquine-resistant malarial para- sites. 4 But, the poor solubility of artemisinin, coupled with its short plasma half life led to a high rate of parasite recrudescence. The development of semi-synthetic analogues through the reduced lac- tone dihydroxyartemisinin gave rise to the oil-soluble derivatives artemether and arteether as well as the water-soluble sodium artesunate. However, the rapid spread of drug resistant malarial strains all over the world forces the search for more selective and effective antimalarial drugs. 5,6 Isolation of new lead compounds from plants is one of the strategies that can be in the search for new drugs. 7–9 Alkaloids of the Amaryllidaceae family exhibit a wide and important range of biological activities. 10–12 For example, narciclasine has shown anticancer activity, 13 and galantamine is a worldwide distributed drug for the treatment of Alzheimer 0 s dis- ease. 14 Some of the Amaryllidaceae alkaloids are also of particular interest because of their potential antimalarial activity: lycorine, haemanthamine, haemanthidine and crinamine possess important activity against several strains of Plasmodium falciparum. 15–17 In the present work we have carried out selective modifications on the structures of three haemanthamine-type alkaloids: hae- manthamine (1), haemanthidine (2) and 11-hydroxyvittatine (3). These alkaloids were isolated in large amounts from the bulbs of Pancratium canariense. 18,19 The 31 obtained derivatives were eval- uated as antimalarial agents against P. falciparum and some preli- minary structure-activity relationships were established for the haemanthamine skeleton. 2. Results and discussion 2.1. Chemistry Alkaloids haemanthamine 1, haemanthidine 2, 11-hydroxyvit- tatine 3, vittatine 4, 8-O-demethylmaritidine 5 and 6-O-methylma- ritidine 6 were isolated from Pancratium canariense as published (Fig 1). 18,19 Modifications achieved on the structure of haemanthamine 1 are shown in Schemes 1 and 2. For the most part, the transformations were carried out on the hydroxyl group at C-11 or on the double bond presents in ring D in order to study their role in the antiplas- modial activity. Compound 7 was obtained quantitatively by acety- lation with acetic anhydride. Esterification with p-vinylbenzoic acid 0968-0896/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bmc.2012.07.036 ⇑ Corresponding authors. E-mail address: aestebra@ull.es (A. Estévez-Braun).   http://www.icic.es Bioorganic & Medicinal Chemistry 20 (2012) 5464–5472 Contents lists available at SciVerse ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc